PROJECT DESCRIPTION Alcohol is the most wildly used substance of abuse. Yet, little is known about the brain effects of blood alcohol concentration (BAC) below the legal limit for driving in the US (17.4 mM or 0.8%). Healthy subjects with BAC as low as 5-10 mM have regional decreases in brain activity, as measured by positron emission tomography after oral administration of [18F]-fluorodeoxyglucose (FDG PET). We have shown that mouse microglial cells treated with high alcohol doses expressed and released cold-inducible RNA-binding protein (CIRP), a novel mediator for neuroinflammation. Mice with BAC equivalent to binge drinking had areas of decreased brain activity, as measured by FDG microPET imaging. CIRP knockout mice exposed to alcohol, however, did not show any decrease in brain activity, suggesting that CIRP is a mediator of the brain activity depression caused by alcohol. Moreover, low dose alcohol (up to 10 mM) produced a dose-dependent increase in the expression of CIRP mRNA and the release of CIRP protein into the culture medium in mouse microglial cell culture. Low dose alcohol also decreased the expression of peroxisome proliferator activated receptor-? (PPAR?), a neuroprotective molecule. Based on our preliminary findings, we hypothesize that low BAC (10 mM or lower) depresses brain activity via the increased expression and release of brain CIRP. We further hypothesize that low BAC-induced downregulation of PPAR? is responsible for the expression and release of brain CIRP into the microenvironment for reducing brain activity. To test these hypotheses, we will determine whether CIRP is responsible for low dose alcohol-induced decreases in brain activity and investigate the mechanism by which low alcohol concentrations increases microglial expression and release of CIRP. These proposed studies will significantly improve our understanding of the mechanism through which CIRP decreases brain activity after consumption of low doses of alcohol. Our research will generate new therapeutic targets with the potential to mitigate brain impairment associated with consumption of alcohol even at low doses.